This project proposes to systematically study relationships between thymoleptic properties of tricyclic antidepressants and their side chain conformations. To this end a large number of rigid structures will be synthesized wherein the side chains are held in various fixed conformations. Ring fusion isomers will be separated by chromatographic techniques and their structures confirmed by x-ray crystallography, nuclear magnetic resonance and/or circular dichroism. The target compounds will be evaluated for antidepressant and behavioral activities in experimental animals, for inhibition of NE and 5-HT uptake, for central anticholinergic-(muscarinic), antiadrenergic and antiserotonergic activities in vivo and in vitro (binding studies), and for displacement of 3H-tricyclic antidepressant binding. Racemic compounds demonstrating significant activity in the above tests will be resolved. The corresponding enantiomers will be evaluated in behavioral and neurochemical tests in search for stereoselective agents with potential utility in stereospecific (SSB) binding studies.